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000139067 245__ $$aTBK1 Mutation Spectrum in an Extended European Patient Cohort with Frontotemporal Dementia and Amyotrophic Lateral Sclerosis.
000139067 260__ $$aNew York, NY [u.a.]$$bWiley-Liss$$c2017
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000139067 520__ $$aWe investigated the mutation spectrum of the TANK-Binding Kinase 1 (TBK1) gene and its associated phenotypic spectrum by exonic resequencing of TBK1 in a cohort of 2,538 patients with frontotemporal dementia (FTD), amyotrophic lateral sclerosis (ALS), or FTD plus ALS, ascertained within the European Early-Onset Dementia Consortium. We assessed pathogenicity of predicted protein-truncating mutations by measuring loss of RNA expression. Functional effect of in-frame amino acid deletions and missense mutations was further explored in vivo on protein level and in vitro by an NFκB-induced luciferase reporter assay and measuring phosphorylated TBK1. The protein-truncating mutations led to the loss of transcript through nonsense-mediated mRNA decay. For the in-frame amino acid deletions, we demonstrated loss of TBK1 or phosphorylated TBK1 protein. An important fraction of the missense mutations compromised NFκB activation indicating that at least some functions of TBK1 are lost. Although missense mutations were also present in controls, over three times more mutations affecting TBK1 functioning were found in the mutation fraction observed in patients only, suggesting high-risk alleles (P = 0.03). Total mutation frequency for confirmed TBK1 LoF mutations in the European cohort was 0.7%, with frequencies in the clinical subgroups of 0.4% in FTD, 1.3% in ALS, and 3.6% in FTD-ALS.
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000139067 542__ $$2Crossref$$i2017-01-19$$uhttp://doi.wiley.com/10.1002/tdm_license_1.1
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000139067 650_7 $$2NLM Chemicals$$aNF-kappa B
000139067 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProtein-Serine-Threonine Kinases
000139067 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aTBK1 protein, human
000139067 650_2 $$2MeSH$$aProtein Serine-Threonine Kinases: genetics
000139067 650_2 $$2MeSH$$aAged
000139067 650_2 $$2MeSH$$aAlleles
000139067 650_2 $$2MeSH$$aAmino Acid Substitution
000139067 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: diagnosis
000139067 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: epidemiology
000139067 650_2 $$2MeSH$$aAmyotrophic Lateral Sclerosis: genetics
000139067 650_2 $$2MeSH$$aCase-Control Studies
000139067 650_2 $$2MeSH$$aCohort Studies
000139067 650_2 $$2MeSH$$aEnzyme Activation
000139067 650_2 $$2MeSH$$aEuropean Continental Ancestry Group: genetics
000139067 650_2 $$2MeSH$$aFemale
000139067 650_2 $$2MeSH$$aFrontotemporal Dementia: diagnosis
000139067 650_2 $$2MeSH$$aFrontotemporal Dementia: epidemiology
000139067 650_2 $$2MeSH$$aFrontotemporal Dementia: genetics
000139067 650_2 $$2MeSH$$aGenetic Association Studies
000139067 650_2 $$2MeSH$$aHeterozygote
000139067 650_2 $$2MeSH$$aHumans
000139067 650_2 $$2MeSH$$aMale
000139067 650_2 $$2MeSH$$aMiddle Aged
000139067 650_2 $$2MeSH$$aMutation
000139067 650_2 $$2MeSH$$aNF-kappa B: metabolism
000139067 650_2 $$2MeSH$$aPhenotype
000139067 650_2 $$2MeSH$$aProtein-Serine-Threonine Kinases: genetics
000139067 650_2 $$2MeSH$$aProtein-Serine-Threonine Kinases: metabolism
000139067 650_2 $$2MeSH$$aSequence Deletion
000139067 650_2 $$2MeSH$$aProtein Serine-Threonine Kinases: metabolism
000139067 650_2 $$2MeSH$$aWhite People: genetics
000139067 7001_ $$aGijselinck, Ilse$$b1
000139067 7001_ $$aVan Mossevelde, Sara$$b2
000139067 7001_ $$aPerrone, Federica$$b3
000139067 7001_ $$aDillen, Lubina$$b4
000139067 7001_ $$aHeeman, Bavo$$b5
000139067 7001_ $$aBäumer, Veerle$$b6
000139067 7001_ $$aEngelborghs, Sebastiaan$$b7
000139067 7001_ $$aDe Bleecker, Jan$$b8
000139067 7001_ $$aBaets, Jonathan$$b9
000139067 7001_ $$aGelpi, Ellen$$b10
000139067 7001_ $$aRojas-García, Ricardo$$b11
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000139067 7001_ $$aAlexopoulos, Panagiotis$$b15
000139067 7001_ $$0P:(DE-HGF)0$$aPerneczky, Robert$$b16
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000139067 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b19$$udzne
000139067 7001_ $$aGraff, Caroline$$b20
000139067 7001_ $$aThonberg, Håkan$$b21
000139067 7001_ $$aBorroni, Barbara$$b22
000139067 7001_ $$aPadovani, Alessandro$$b23
000139067 7001_ $$aJordanova, Albena$$b24
000139067 7001_ $$aSarafov, Stayko$$b25
000139067 7001_ $$aTournev, Ivailo$$b26
000139067 7001_ $$ade Mendonça, Alexandre$$b27
000139067 7001_ $$aMiltenberger-Miltényi, Gabriel$$b28
000139067 7001_ $$aSimões do Couto, Frederico$$b29
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000139067 7001_ $$aCras, Patrick$$b35
000139067 7001_ $$aVandenberghe, Rik$$b36
000139067 7001_ $$aDe Jonghe, Peter$$b37
000139067 7001_ $$aDe Deyn, Peter P$$b38
000139067 7001_ $$aSleegers, Kristel$$b39
000139067 7001_ $$aCruts, Marc$$b40
000139067 7001_ $$0P:(DE-HGF)0$$aVan Broeckhoven, Christine$$b41$$eCorresponding author
000139067 7001_ $$aGoeman, Johan$$b42
000139067 7001_ $$aNuytten, Dirk$$b43
000139067 7001_ $$aSmets, Katrien$$b44
000139067 7001_ $$aRobberecht, Wim$$b45
000139067 7001_ $$aDamme, Philip Van$$b46
000139067 7001_ $$aBleecker, Jan De$$b47
000139067 7001_ $$aSantens, Patrick$$b48
000139067 7001_ $$aDermaut, Bart$$b49
000139067 7001_ $$aVersijpt, Jan$$b50
000139067 7001_ $$aMichotte, Alex$$b51
000139067 7001_ $$aIvanoiu, Adrian$$b52
000139067 7001_ $$aDeryck, Olivier$$b53
000139067 7001_ $$aBergmans, Bruno$$b54
000139067 7001_ $$aDelbeck, Jean$$b55
000139067 7001_ $$aBruyland, Marc$$b56
000139067 7001_ $$aWillems, Christiana$$b57
000139067 7001_ $$aSalmon, Eric$$b58
000139067 7001_ $$aPastor, Pau$$b59
000139067 7001_ $$aOrtega-Cubero, Sara$$b60
000139067 7001_ $$aBenussi, Luisa$$b61
000139067 7001_ $$aGhidoni, Roberta$$b62
000139067 7001_ $$aBinetti, Giuliano$$b63
000139067 7001_ $$aHernández, Isabel$$b64
000139067 7001_ $$aBoada, Mercè$$b65
000139067 7001_ $$aRuiz, Agustín$$b66
000139067 7001_ $$aSorbi, Sandro$$b67
000139067 7001_ $$aNacmias, Benedetta$$b68
000139067 7001_ $$aBagnoli, Silvia$$b69
000139067 7001_ $$aSorbi, Sandro$$b70
000139067 7001_ $$aSanchez-Valle, Raquel$$b71
000139067 7001_ $$aLlado, Albert$$b72
000139067 7001_ $$aSantana, Isabel$$b73
000139067 7001_ $$aRosário Almeida, Maria$$b74
000139067 7001_ $$aFrisoni, Giovanni B$$b75
000139067 7001_ $$0P:(DE-HGF)0$$aMaetzler, Walter$$b76
000139067 7001_ $$aMatej, Radoslav$$b77
000139067 7001_ $$aFraidakis, Matthew J$$b78
000139067 7001_ $$aKovacs, Gabor G$$b79
000139067 7001_ $$aFabrizi, Gian Maria$$b80
000139067 7001_ $$aTesti, Silvia$$b81
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